Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia

Abstract

Introduction Neonates with hypoxic‐ischemic encephalopathy (HIE) undergoing hypothermia may benefit from adjunctive therapy with melatonin. However, melatonin safety, pharmacokinetics (PK), and dosage in this sensitive population are still unknown. Methods and results This study assessed the PK and safety of melatonin enteral administration to neonates with HIE undergoing hypothermia. Melatonin was infused at 0.5 mg/kg in five neonates with HIE undergoing hypothermia. Infusion started 1 hour after the neonates reached the target temperature of 33.5°C. Blood samples were collected before and at selective times after melatonin infusion. Abdominal complications or clinically significant changes in patients’ vital signs were not found during or after melatonin. The peak plasma concentration reached 0.25 µg/mL. The area under the curve in 24 hours was 4.35 µg/mL*h. Discussion Melatonin half‐life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK. In humans high blood concentrations with lower doses can be achieved compared to animal experimentation, although intravenous administration is advised in the neonate population. Our study is a preparatory step for future clinical studies aimed at assessing melatonin efficacy in HIE.

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

“…It is feasible that in babies with NE, resuscitation would be completed and venous access in place by 1 h, enabling the start of melatonin infusion. Oral melatonin has been used in NE babies undergoing HT and is absorbed 33,34 , however for rapid achievement of therapeutic levels and optimal protection, intravenous administration is more reliable. In the piglet model we have observed that brain protection is dependent on the time after HI that therapeutic levels are achieved 14 .…”

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

“…Brain or whole-body hypothermia is currently the only therapeutic option offering amelioration in the prognosis, as from preclinical and clinical data [26,[43][44][45]. In addition, evidence of a benefit from adjunctive therapy with melatonin has been described [46,47], and a recent study on melatonin safety, pharmacokinetics (PK), and dosage in the neonatal population reported positive results [25]. Finally, it is worth noting that a significant increase of melatonin was described following hypoxia both in experimental models and in human stroke, suggesting even the existence of an endogenous protective response on its part [48].…”

“…Particularly relevant is the beneficial potential of melatonin in perinatal hypoxia. Melatonin has been previously used in association with the standard hypothermic therapy in newborns affected by hypoxia, with positive results [24][25][26].…”

Melatonin: new insights on its therapeutic properties in diabetic complications

“…Since melatonin is mainly metabolized by cytochrome P450 (CYP) 1A2 and CYP2C19, inhibitors of these enzymes lead to higher concentration of melatonin in the body [42]. Melatonin lowers blood pressure and glucose level, therefore, patients receiving antihypertensive or blood glucose lowering drugs should use melatonin with cautious [43]. Since the administration of melatonin during pregnancy is not studied, its use is not recommended for pregnant women [38].…”

“…Of note, melatonin elimination occurs faster in children in comparison to adults [54]. Low absorption from the gastrointestinal tract, high first-pass effect and high rate of metabolizing make melatonin a drug with low [43,55].…”